Circulating DNA and Protein Biomarkers May Be Associated With Benefit of Regorafenib in Metastatic Colorectal Cancer
In a retrospective study reported in The Lancet Oncology, Tabernero et al used commercially available BEAMing technology to assess plasma tumor DNA and protein levels in a subgroup of patients from the CORRECT trial of regorafenib (Stivarga) in metastatic colorectal cancer and examined the association of these biomarkers with treatment outcome. Results indicated that regorafenib benefit was consistent across mutation and protein concentration status. BEAMing is based on emulsion polymerase chain reaction and permits detection of 1 mutant allele in 10,000 wild-type alleles. Regorafenib was associated with significant improvement in overall survival vs placebo in this trial.
Study Details
In the study, BEAMing technology was used to identify KRAS, PIK3CA, and BRAF mutations in DNA obtained from plasma of 503 patients. Concentrations of 15 proteins of interest (angiopoietin 2, interleukin 6, interleukin 8, placental growth factor, soluble TIE-1, soluble VEGFR1, VEGF-A, VEGF-C, VEGF-D, VEGF-A isoform 121, bone morphogenetic protein 7, macrophage colony-stimulating factor, stromal cell-derived factor-1, tissue inhibitor of metalloproteinase 2, and von Willebrand factor) were also measured in plasma from 611 patients.
Association With Clinical Outcome
Overall, KRAS mutations were identified in 69% of patients; PIK3CA mutations, in 17%; and BRAF mutations, in 3%. Correlative analysis for BRAF genotype was not performed due to the low mutational frequency. Correlative analysis indicated consistent benefit of regorafenib for KRAS and PIK3CA mutant and wild-type subgroups.
Hazard ratios (HR) for progression-free survival for regorafenib vs placebo were 0.52 (95% confidence interval [CI] = 0.35–0.76) for wild-type KRAS and 0.51 (95% CI = 0.40–0.65) for mutant KRAS (P for interaction = .74); and 0.50 (95% CI = 0.40–0.63) for wild-type PIK3CA and 0.54 (95% CI = 0.32–0.89) for mutant PIK3CA (P for interaction = .85). Hazard ratios were 0.53 (95% CI = 0.40–0.71) for low circulating DNA concentrations and 0.52 (95% CI = 0.40–0.70) for high concentrations (P for interaction = .601).
In univariate analysis, the only plasma protein associated with differing hazard ratios for regorafenib vs placebo according to high vs low concentration was TIE-1 (with high concentration being associated with longer overall survival but not progression-free survival); however, the association was not significant on multivariate analysis.
The investigators concluded: “BEAMing of circulating DNA could be a viable approach for noninvasive analysis of tumour genotype in real time and for the identification of potentially clinically relevant mutations that are not detected in archival tissue. Additionally, the results show that regorafenib seems to be consistently associated with a clinical benefit in a range of patient subgroups based on mutational status and protein biomarker concentrations.”
Josep Tabernero, MD, of Vall d’Hebron University Hospital and Institute of Oncology, Universitat Autonoma de Barcelona, is the corresponding author of The Lancet Oncology article.
The study was supported by Bayer HealthCare Pharmaceuticals. For full disclosures of the study authors, visit www.thelancet.com.
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